Atrial septal defect 7

Summary

Atrial septal defect 7 (MONDO:0007173) is a disease caused by NKX2-5 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NKX2-5 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 561
• Phenotypes (HPO): 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		11	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

3 HPO clinical features (Orphanet curated; top 3 by frequency):

HPO ID	Term	Frequency
HP:0001671	Abnormal cardiac septum morphology	Very frequent (80-99%)
HP:0011675	Arrhythmia	Very frequent (80-99%)
HP:0011710	Bundle branch block	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	atrial septal defect 7
Mondo ID	MONDO:0007173
OMIM	108900
Orphanet	1479
DOID	DOID:0110112
UMLS	C3276096
MedGen	477726
GARD	0016566
Is cancer (heuristic)	no

Also known as: ASD with or without atrioventricular conduction defects · ASD7 · atrial heart septal defect caused by mutation in NKX2-5 · atrial heart septal defect type 7 · atrial septal defect 7 with or without atrioventricular conduction defects · atrial septal defect-atrioventricular conduction defects syndrome · NKX2-5 atrial heart septal defect

Data availability: 561 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › congenital heart disease › heart septal defect › atrial septal defect › atrial septal defect 7

Related subtypes (14): Lutembacher syndrome, atrial septal defect 1, atrial septal defect 2, atrial septal defect 4, atrial septal defect 5, atrial septal defect 6, atrial septal defect 3, atrial septal defect 8, atrial septal defect 9, atrial septal defect, ostium secundum type, atrial septal defect, coronary sinus type, atrial septal defect, sinus venosus type, atrial septal defect, ostium primum type, patent foramen ovale

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

561 retrieved; paginated sample, class counts are floors:

254 uncertain significance, 152 likely benign, 81 pathogenic, 43 conflicting classifications of pathogenicity, 9 likely pathogenic, 9 benign/likely benign, 8 pathogenic/likely pathogenic, 5 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2425102	NC_000005.9:g.(?172089144)(172774583_?)del	ATP6V0E1	Pathogenic	criteria provided, single submitter
3246360	NC_000005.9:g.(?171765373)(172662086_?)del	ATP6V0E1	Pathogenic	criteria provided, single submitter
692223	GRCh37/hg19 5q34-35.2(chr5:166421173-173324843)x1	ATP6V0E1	Pathogenic	criteria provided, single submitter
1068493	NM_004387.4(NKX2-5):c.270del (p.Ala91fs)	NKX2-5	Pathogenic	criteria provided, single submitter
1069411	NM_004387.4(NKX2-5):c.281del (p.Pro94fs)	NKX2-5	Pathogenic	criteria provided, single submitter
1071005	NM_004387.4(NKX2-5):c.462del (p.Glu154fs)	NKX2-5	Pathogenic	criteria provided, single submitter
1072792	NM_004387.4(NKX2-5):c.598_599del (p.Gln200fs)	NKX2-5	Pathogenic	criteria provided, single submitter
1299661	NM_004387.4(NKX2-5):c.261del (p.Ala88fs)	NKX2-5	Pathogenic	no assertion criteria provided
1358436	NM_004387.4(NKX2-5):c.377_378del (p.Glu126fs)	NKX2-5	Pathogenic	criteria provided, single submitter
1364905	NM_004387.4(NKX2-5):c.340_341del (p.Cys114fs)	NKX2-5	Pathogenic	criteria provided, single submitter
1375957	NM_004387.4(NKX2-5):c.340_341dup (p.Leu116fs)	NKX2-5	Pathogenic	criteria provided, single submitter
1381333	NM_004387.4(NKX2-5):c.434dup (p.Ser146fs)	NKX2-5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1401094	NM_004387.4(NKX2-5):c.585del (p.Gln196fs)	NKX2-5	Pathogenic	criteria provided, single submitter
1409300	NM_004387.4(NKX2-5):c.744C>A (p.Tyr248Ter)	NKX2-5	Pathogenic	criteria provided, single submitter
1417309	NM_004387.4(NKX2-5):c.437C>A (p.Ser146Ter)	NKX2-5	Pathogenic	criteria provided, multiple submitters, no conflicts
1432308	NM_004387.4(NKX2-5):c.212del (p.Ala71fs)	NKX2-5	Pathogenic	criteria provided, multiple submitters, no conflicts
1432865	NM_004387.4(NKX2-5):c.423dup (p.Arg142fs)	NKX2-5	Pathogenic	criteria provided, single submitter
1441437	NM_004387.4(NKX2-5):c.167_186dup (p.Ala63fs)	NKX2-5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1443937	NM_004387.4(NKX2-5):c.253_256dup (p.Phe86fs)	NKX2-5	Pathogenic	criteria provided, single submitter
1451578	NM_004387.4(NKX2-5):c.512T>C (p.Leu171Pro)	NKX2-5	Pathogenic	criteria provided, multiple submitters, no conflicts
1452531	NM_004387.4(NKX2-5):c.270dup (p.Ala91fs)	NKX2-5	Pathogenic	criteria provided, multiple submitters, no conflicts
1452571	NM_004387.4(NKX2-5):c.230del (p.Pro77fs)	NKX2-5	Pathogenic	criteria provided, single submitter
1456175	NM_004387.4(NKX2-5):c.778_784dup (p.Ala262fs)	NKX2-5	Pathogenic	criteria provided, single submitter
1515823	NM_004387.4(NKX2-5):c.433T>C (p.Phe145Leu)	NKX2-5	Pathogenic	criteria provided, single submitter
156158	NM_004387.4(NKX2-5):c.461A>G (p.Glu154Gly)	NKX2-5	Pathogenic	no assertion criteria provided
156159	NM_004387.4(NKX2-5):c.618del (p.Leu207fs)	NKX2-5	Pathogenic	no assertion criteria provided
156160	NM_004387.4(NKX2-5):c.721_728del (p.Tyr241fs)	NKX2-5	Pathogenic	no assertion criteria provided
159257	NM_004387.4(NKX2-5):c.783del (p.Ala262fs)	NKX2-5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805774	NM_004387.4(NKX2-5):c.487del (p.Leu163fs)	NKX2-5	Pathogenic	criteria provided, single submitter
1993512	NM_004387.4(NKX2-5):c.328A>T (p.Lys110Ter)	NKX2-5	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NKX2-5	Definitive	Autosomal dominant	atrial septal defect 7	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NKX2-5	Orphanet:101351	Familial isolated congenital asplenia
NKX2-5	Orphanet:1479	Atrial septal defect-atrioventricular conduction defects syndrome
NKX2-5	Orphanet:1627	Deletion 5q35 syndrome
NKX2-5	Orphanet:2248	Hypoplastic left heart syndrome
NKX2-5	Orphanet:3303	Tetralogy of Fallot
NKX2-5	Orphanet:334	Hereditary atrial fibrillation
NKX2-5	Orphanet:402075	Familial bicuspid aortic valve
NKX2-5	Orphanet:871	Hereditary progressive cardiac conduction defect
NKX2-5	Orphanet:95712	Thyroid ectopia
NKX2-5	Orphanet:95713	Athyreosis
NKX2-5	Orphanet:99103	Atrial septal defect, ostium secundum type

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NKX2-5	HGNC:2488	ENSG00000183072	P52952	Homeobox protein Nkx-2.5	gencc,clinvar
ATP6V0E1	HGNC:863	ENSG00000113732	O15342	V-type proton ATPase subunit e 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NKX2-5	Homeobox protein Nkx-2.5	Transcription factor required for the development of the heart and the spleen.
ATP6V0E1	V-type proton ATPase subunit e 1	Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NKX2-5	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
ATP6V0E1	Other/Unknown	no		ATPase_V0-cplx_e1/e2_su, ATPase_V0-cplx_e1/e2_su_met

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
cardiac atrium	1
right atrium auricular region	1
corpus epididymis	1
epithelium of nasopharynx	1
nasopharynx	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NKX2-5	98	broad	yes	apex of heart, right atrium auricular region, cardiac atrium
ATP6V0E1	305	ubiquitous	marker	epithelium of nasopharynx, nasopharynx, corpus epididymis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NKX2-5	2,355
ATP6V0E1	949

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATP6V0E1	O15342	9
NKX2-5	P52952	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	380.7×	0.008	NKX2-5
Physiological factors	1	335.9×	0.008	NKX2-5
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	335.9×	0.008	ATP6V0E1
Cardiogenesis	1	211.5×	0.008	NKX2-5
Insulin receptor recycling	1	190.3×	0.008	ATP6V0E1
Transferrin endocytosis and recycling	1	184.2×	0.008	ATP6V0E1
ROS and RNS production in phagocytes	1	167.9×	0.008	ATP6V0E1
Amino acids regulate mTORC1	1	100.2×	0.011	ATP6V0E1
Ion channel transport	1	48.0×	0.021	ATP6V0E1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
Purkinje myocyte differentiation	1	8426.0×	0.002	NKX2-5
septum secundum development	1	8426.0×	0.002	NKX2-5
right ventricular cardiac muscle tissue morphogenesis	1	4213.0×	0.002	NKX2-5
atrioventricular node cell fate commitment	1	4213.0×	0.002	NKX2-5
cardiac ventricle formation	1	2808.7×	0.002	NKX2-5
apoptotic process involved in heart morphogenesis	1	2808.7×	0.002	NKX2-5
proepicardium development	1	2808.7×	0.002	NKX2-5
pulmonary myocardium development	1	2808.7×	0.002	NKX2-5
ventricular cardiac myofibril assembly	1	2808.7×	0.002	NKX2-5
atrial cardiac muscle cell development	1	2808.7×	0.002	NKX2-5
bundle of His development	1	2106.5×	0.002	NKX2-5
atrial cardiac muscle tissue development	1	2106.5×	0.002	NKX2-5
positive regulation of cardioblast differentiation	1	2106.5×	0.002	NKX2-5
atrioventricular node cell development	1	2106.5×	0.002	NKX2-5
regulation of cardiac muscle cell proliferation	1	1685.2×	0.003	NKX2-5
atrioventricular node development	1	1404.3×	0.003	NKX2-5
embryonic heart tube left/right pattern formation	1	1404.3×	0.003	NKX2-5
positive regulation of heart contraction	1	1053.2×	0.004	NKX2-5
ventricular cardiac muscle cell development	1	766.0×	0.005	NKX2-5
cardiac muscle tissue morphogenesis	1	702.2×	0.005	NKX2-5
atrial septum morphogenesis	1	648.1×	0.005	NKX2-5
adult heart development	1	601.9×	0.005	NKX2-5
cardiac septum morphogenesis	1	601.9×	0.005	NKX2-5
negative regulation of epithelial cell apoptotic process	1	601.9×	0.005	NKX2-5
negative regulation of myotube differentiation	1	561.7×	0.005	NKX2-5
heart trabecula formation	1	561.7×	0.005	NKX2-5
cardiac conduction system development	1	526.6×	0.005	NKX2-5
ventricular trabecula myocardium morphogenesis	1	526.6×	0.005	NKX2-5
regulation of cardiac muscle contraction	1	443.5×	0.005	NKX2-5
positive regulation of sodium ion transport	1	421.3×	0.005	NKX2-5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NKX2-5	0	0
ATP6V0E1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	NKX2-5, ATP6V0E1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
NKX2-5	0	—
ATP6V0E1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.